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Summary of Advances Cover 2014

Summary of Advances

In Autism Spectrum Disorder Research


Question 2: How Can I Understand What Is Happening?

Synaptic, transcriptional and chromatin genes disrupted in autism
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma’ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK; DDD Study; Homozygosity Mapping Collaborative for Autism; UK10K Consortium, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD. Nature. 2014 Nov;515(7526):209-15. [PMID: 25363760]

Hundreds of genes are affected by genetic mutations associated with ASD. In this study, the researchers were interested in identifying and analyzing genes with either inherited or spontaneous (de novo) mutations that reduced or eliminated the gene’ s normal function, known as loss of function (LoF) mutations. The researchers analyzed the genomes of more than 15,400 individuals with and without ASD, making it one of the largest studies of its kind. DNA samples from ASD family “trios” (two parents with a single child with ASD) were examined; an unexpectedly high percentage of the families contained de novo LoF mutations, leading the researchers to conclude that the most promising way to identify ASD-associated genes would be to analyze spontaneous and inherited genetic mutations in both individuals with and without ASD. Using this analytical method and controlling strictly for false discoveries, researchers identified 33 genes potentially associated with ASD risk. Fifteen of these genes were already known to be associated with ASD risk, 11 were suspected to play a role in ASD based on previous studies, and seven were seen in this study for the first time. De novo mutations in these 33 genes, which are believed to have a large effect on ASD risk, were observed at a higher frequency in females with ASD than males with ASD; this supports the idea that females may be in part “protected” from ASD. LoF variations in this group of genes were unlikely to be inherited from parents without ASD, meaning they were more likely to appear as de novo mutations in individuals with ASD.

Adjusting their analysis to control less strictly for false discoveries, the researchers identified 107 genes potentially associated with ASD. They found that more than 5% of the individuals with ASD in this study had a de novo LoF mutation in at least one of these genes. The LoF alterations in this second group of genes were more likely to be inherited from the parents than to arise spontaneously in individuals with ASD. Of the 107 genes, the researchers found an overrepresentation of genes involved in biological pathways important for healthy brain development. Furthermore, the researchers used a database to categorize a number of the genes as potentially involved in other disorders; these included 21 candidate genes for intellectual disability, three for epilepsy, 17 for schizophrenia, nine for congenital heart disease, and six for metabolic disorders.

To find other genes that potentially contribute to ASD risk, researchers looked for clusters of gene variations thought to be most harmful to neurodevelopment based on where in the brain they are expressed (“ turned on”). This analysis identified 160 genes that may affect risk, including genes related to cell-to-cell communication (synaptic function) and regulation of gene expression (regulation of when and how often genes are “turned on”), which are processes essential to normal brain development. This study furthers our understanding of how genetic factors contribute to the development of ASD, and the identification of specific ASD-associated genes implicates specific biological pathways that can be the focus of further research.

Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection
Fraizer TW, Georgiades S, Bishop SL, Harden, AY. J Am Acad Child Adolesc Psychiatry. 2014 Mar;53(3):329-40. e1-3. [PMID: 24565360]

Males are at higher risk for ASD than females, so most characteristics that define the disorder are based on studies of males. If females with ASD have characteristics that differ from those seen in males, their symptoms may go unrecognized and females may be underdiagnosed. In the largest and most comprehensive study to date on females with ASD, researchers compared behavioral and cognitive characteristic of boys and girls with ASD, drawing on the Simons Simplex Collection (SSC) of more than 2,000 males and 300 females with ASD, 4 to 18 years of age. The researchers analyzed (1) core autism symptoms, (2) cognitive and motor function, and (3) adaptive behavior (social and practical skills) (4) and associated behavior problems. Regarding core autism symptoms, females showed higher levels of communication impairments, but they have lower levels of repetitive behavior symptoms. In fact, the largest difference between males and females in this study concerned restricted interests (high levels of intensity or focus on topics or objects). Females showed worse adaptive behavior in all areas, as well as greater associated behavior problems, such as irritability and lethargy. On measures of cognition and motor function, females showed lower overall, verbal, and nonverbal cognitive scores, as well as reduced language scores. Boys and girls were comparable on measures of motor function. However, males showed a greater discrepancy between verbal and nonverbal IQ, with the nonverbal IQ scoring higher, whereas females showed a discrepancy in favor of the verbal. Given this discrepancy, researchers also showed that lower IQ in females accounted for other observed differences, specifically, higher social communication impairments and lower adaptive function. IQ did not account for either the lower occurrence of restricted interests or the greater irritability and externalizing behaviors (such as aggression and acting out) in females. The study confirms findings from previous smaller studies that indicated females diagnosed with ASD tend to have generally greater impairments than males, including more social communication, cognitive, language, adaptive function, and behavioral challenges. The study also raises the question of whether high-functioning females with ASD are under-identified because they may have lower levels of symptoms (such as restricted interests) that are commonly seen in males with ASD. Clinicians should be aware that symptom disparities exist between females and males with ASD, and further study is needed to understand sex differences in ASD, including more focused studies of symptom disparities and the association of sex differences with genetic variation.

A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders
Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, Beckmann JS, Rosenfeld JA, Eichler EE. Am J Hum Genet. 2014 Mar 6;94(3):415-25. [PMID: 24581740]

More males than females have ASD, intellectual disabilities, and other neurodevelopmental disorders, which raises the question of whether females benefit from biological mechanisms that provide “protection” from such disorders. Past studies have shown mixed results, which may be due to sample size and differing methodologies. To address these concerns and to test for a “female protective model,” researchers analyzed DNA samples from two groups of people with neurological conditions. The first group consisted of DNA from more than 9,200 males and 6,300 females who had undergone genetic testing because of a suspected developmental disability (DD), intellectual disability (ID), or ASD. The second group consisted of DNA samples from the Swedish Simons Simplex Collection (SSC). (Simplex families are those with only one individual with ASD.) The researchers compared the DNA from these two groups to the DNA of people who were not suspected of having any neurological disorder (all groups were overwhelmingly of European ancestry). The researchers speculated that a protective effect for females would appear as an increased number of harmful genetic mutations in females (compared with males) with neurological disorders. In other words, if females are indeed protected, they would need to possess a larger number of harmful genetic alterations than males do before showing symptoms, and this is precisely what this study found. At the same time and also as expected, females with genetic alterations associated with neurodevelopmental disorders showed more severe symptoms, such as low IQ. Compared with males, females with neurological disorders were shown to have two to three times more genes harmed, as well as more serious alterations to the individual genes affected. This increased burden of genetic mutations remained even when controlling for cognitive ability, measured by IQ, which indicates that other traits besides cognition may also be associated with the increased mutational burden observed in females. Genetic alterations associated with ASD were also more likely to be inherited from the mother than from the father, and alterations inherited from the mother were more harmful than genetic alterations inherited from the father. The researchers found that females carried a larger number of harmful genetic mutations, whether they were parents or offspring, lending credence to the idea that females are biologically protected from some neurological disorders. Stated another way, symptoms of ASD and other disorders will be observable in maleswith comparatively mild genetic alterations, whereas a female with the same scope or severity of genetic alteration may not show classic symptoms. Further research to elucidate the mechanisms of this neuroprotective effect may be helpful for increasing the understanding of sex differences in autism and future development of approaches to reduce the most disabling symptoms of ASD.

Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis
McElhanon BO, McCracken C, Karpen S, Sharp WG. Pediatrics. 2014 May;133(5):872-83. [PMID: 24777214]

Gastrointestinal (GI) dysfunction is frequently diagnosed in children with ASD. GI dysfunction is of particularconcern in an ASD population due to their increased risk of feeding problems, most notably food selectivity (in which an individual eats only a narrow variety of foods). While this may not be an initial cause of concern, it can lead to multiple co-morbid health conditions (i.e. malnutrition or obesity). Many theories exist about possible connections between GI dysfunction and ASD, including that GI abnormality may be associated with ASD through some pathway that involves abnormality in the immune system; however, the underlying mechanisms and prevalence remain unclear.

To determine the overall difference in GI symptoms between children with and children without ASD, the current study conducted a meta-analysis of medical research into GI diagnoses, signs, and symptoms. The researchers searched multiple scholarly databases for relevant peer-reviewed research that involved collecting and analyzing data on GI symptoms and problems from appropriate subjects (children birth to 18 years with ASD); involved non-ASD comparison groups; and presented data on GI symptoms in credible ways. Fifteen studies meeting these criteria were then analyzed for their findings. Across these studies, the researchers found that children with ASD experienced significantly more general GI concerns, diarrhea, constipation, and abdominal pain than comparison children. The odds of children with ASD having general GI symptoms may have been four times higher than for children without ASD. A limitation of this study is that only four of 15 identified GI symptoms had enough prior published research to be included in this study. The researchers concluded that this indicates a need for more systematic and comprehensive research to identify the causes and long-term impacts of GI symptoms in ASD. Parents and clinicians should be aware of the increased risk of GI dysfunction in children on the autism spectrum, and there is a need for best practices and increased flexibility in the treatment of GI issues in this population.

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW. Am J Hum Genet. 2014 May 1;94(5):677-94. [PMID: 24768552]

Some individuals with ASD carry genetic mutations consisting of duplicated or deleted genes. These copy-number variations (CNVs), as they are known, can be either inherited or de novo (spontaneous, and therefore not inherited). In this study, the researchers were particularly interested in rare CNVs (those occurring in less than 1% of cases). DNA samples of 2,446 individuals with ASD and their parents were compared to a “control” group consisting of 2,640 individuals to analyze and measure the impact of CNVs on ASD. Not all genetic mutations are harmful, so regardless of the subject’s ASD status, the researchers used information from previous studies to classify each CN mutation they found as pathologic (disease-related), benign (not harmful), or “uncertain.” The researchers found that individuals with ASD had about 1.4 times as many genes affected by rare duplication and deletion CNVs than individuals without ASD. The study also showed that most (64%) of the pathogenic CNVs in people with ASD were de novo (spontaneously occurring), while 36% were inherited. The researchers also looked for differences between males and females with ASD. They found that, when compared with the 6:1 ratio of males to females in the ASD group, the subgroup of subjects with ASD that had very harmful CNVs was composed of an increased proportion of females (a male-to-female ratio of 2:1). In addition, the researchers observed that females were nearly twice as likely as males to have CNVs in a specific set of genes associated with low cognitive functioning; this lends support to the hypothesis of a “female protective effect,” which postulates that the number of mutations present in these genes must reach a high threshold in girls in order to result in ASD symptoms.

This study also looked at the kinds of genes affected by CNVs in individuals with ASD; this allows scientists to identify the underlying biological pathways that may be altered in ASD. Upon specifically examining genes important for brain function, the researchers found that a larger number of these genes were affected by rare deletion- and duplication-type CNVs in subjects with ASD compared with those in the control group. The researchers also found that rare genetic mutations associated with ASD appear to converge in networks of genes central to key biological processes, such as brain development, function of synapses (the small junctures between neurons), as well as chromatin and transcription regulation (important for determining whether genes are “turned on” or “turned off”). Overall, the results of this study confirm previous research suggesting there are likely many genes and areas of the genome that may be implicated in autism. Although rare mutations associated with ASD can occur in hundreds of genes, many of these mutations affect particular biological mechanisms, which offer potential targets for future research.

Question 2

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